1. Field of the Invention
The present invention relates to methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), including methods and compositions for using this receptor, as well as agonists and antagonists of MIF which bind to this receptor or which otherwise modulate the interaction of MIF with CD74 or the consequences of such interaction, in methods for treatment of conditions characterized by locally or systemically altered MIF levels, particularly inflammatory conditions and cancer.
2. Background of the Technology
Macrophage migration inhibitory factor (MIF), the first cytokine activity to be described, has emerged to be seen as a critical regulator of the innate and adaptive immune response1-3. MIF is encoded by a unique gene, and crystallization studies have shown MIF to define a new protein fold and structural superfamily4. Despite the fact that the biological activity attributed to MIF first was described almost 30 years ago, information regarding MIF's precise role in cell physiology and immunity has emerged only recently1-9,18. MIF is centrally involved in macrophage and T cell activation and in the development of septic shock, arthritis, and other inflammatory conditions2. Also, MIF has been linked to cancer32.
MIF is critically involved in the expression of innate and acquired immunity. MIF is released by a variety of cell types and is a necessary factor for the activation or proliferative responses of macrophages18, T cells6, and fibroblasts7. MIF's mitogenic effects proceed via an autocrine/paracrine activation pathway involving the p44/p42 (ERK-1/2) mitogen-activated protein kinase cascade7. MIF −/− mice are highly resistant to endotoxic shock3, and immunoneutralization of MIF confers protection against septic shock25 and a variety of immuno-inflammatory pathologies such as delayed-type hypersensitivity26, arthritis27, and glomerulonephritis28. MIF's actions on cells also show a number of unique features. These include a global, counter-regulatory action on glucocorticoid-induced immunosuppression5,6, the induction of a sustained pattern of ERK-1/2 activation7, and functional antagonism of p53-dependent apoptosis6.
MIF's pro-inflammatory properties have been linked to its capacity to counter-regulate the immunosuppressive effects of glucocorticoids5,6, and its interactions with cells have been presumed to require a receptor-based mechanism of action7,8 or to reflect a specialized, intracellular mode of action9. Numerous in vitro and in vivo studies have been consistent with MIF acting by engagement of a cell surface receptor, however lack of progress toward the identification of candidate receptors has prompted interest in either specialized, intracellular modes of action9 or the potential biological role of MIF's tautomerase activity2,21. There also is evidence that MIF may function as an isomerase4.
The MHC class II-associated invariant chain, Ii (CD74)10, has been established to play an important role in the processing and transport of MHC class II proteins from the endoplasmic reticulum to the Golgi10. Most Ii dissociates from the class II complex as antigenic peptides load onto their class II binding sites. Approximately 2-5% of total cellular Ii also is expressed on the cell surface, where it has been shown to function as an accessory molecule for T cell activation11. Ii has been previously implicated in signaling and accessory functions for immune cell activation11-13.
U.S. Pat. No. 5,559,028 to Humphreys, et al. discloses gene constructs for expression of wild type and mutant Ii chains in recombinant cells. U.S. Pat. No. 5,726,020 to Humphreys, et al. discloses and claims expressible reverse gene constructs and oligonucleotides that hybridize with an Ii mRNA molecule, thereby inhibiting translation of the Ii mRNA molecule.